This multidisciplinary research program combines various analytic techniques to investigate the synaptic physiology, biophysics, and biochemistry of epileptogenesis and the development of the epileptic process in mammalian brain. The goal is to apply new methods of selectively measuring excitability changes at excitatory synapses, second-messenger modulation of inhibitory synaptic transmission, and axonal sprouting in specific neural networks to determine whether key excitability defects in epileptic brain are mediated by use-dependent and potentially reversible mechanisms. The research tests specific hypotheses extending from the molecular to the structural levels of neural organization, and is based on three model systems. (1) Acute epileptogenesis, using hippocampal slice techniques, will be studied with a focus on the immediate role of use-dependent plastic properties of recurrent excitatory synapses in the CA3 subfield and on long-term potentiation in the generation of epileptiform activity. (2) Chronic focal epileptogenesis, using slices from kindled animals, will be studied to determine the functional consequences of aberrant mossy fiber growth during prolonged abnormal stimulation. (3) Inherited generalized epileptogenesis, using slices from epileptic mice with single-locus genetic mutations, will be studied to examine synaptic and biochemical mechanisms underlying network bursting, modulation of GABA- receptor-mediated inhibition, and aberrant axonal sprouting and neosynaptogenesis. A critical element of this research program is the high degree of interaction and collaboration, at both technical and conceptual levels, among the scientists who comprise the research team.